Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disease characterized by cognitive decline, and at autopsy, its distinct brain pathologies, neurofibrillary tangles and neuritic plaques. The major protein component of neuritic plaques is a peptide known as amyloid _ (A_), mechanistically linked to AD by virtue of mutations in its precursor protein (APP). The objective of this research is to define the structure of A_ aggregates and precisely determine the molecular interactions responsible for AD-relevant neuronal responses elicited by A_. A further objective is to characterize structural aspects of A_ interactions with two other plaque components, apolipoprotein E (apoE) and apoJ, which are elevated in AD brain tissue. Definition of molecular interactions linked to AD-relevant neuronal responses is essential for identification of drug targets to slow or block the progression of disease pathology. Mass spectrometric techniques are crucial t o t hesemechanistic studies.